Obesity is a global issue. Life-threatening medical disorders associated with obesity include cardiovascular disease, type 2 diabetes, and likely certain types of cancer; these would be minimized if obesity could be better controlled. In addition, healthcare costs would be increasingly manageable in proportion to the reduction in obesity. To supplement diet- and exercise-based measures to control obesity, various drugs have been developed. Most currently approved drugs, such as lorcaserin (Belviq) and phentermine-topiramate (Qsymia), rely on appetite suppression and subsequent reduced food intake, while another, orlistat (marketed as Xenical and Alli), works by reducing fat absorption. In addition to being limited to populations of susceptible patients, weight-loss drugs are compromised by side-effects (often cardiovascular or psychiatric). Thus, additional, novel therapeutics are being sought to combat obesity, focusing on molecular mechanisms, for example, ubiquitylation/deubiquitylation, that can be affected pharmacologically to halt or reverse accumulation of excess fat. Ubiquitin conjugating enzymes, known as E3 ligases, are a very large (~600) family of enzymes, many of which have been linked genetically and/or biochemically to various pathologies. One ligase, HRD1, is associated with adipose tissue; knockout or knockdown of this ligase in mice leads to a large reduction in white adipose and weight loss. Its ubiquitylation target appears to be PCG1?, a transcriptional co-activator involve in fatty acid metabolism and mitochondrial biogenesis. It is therefore proposed here to develop small molecule inhibitors of HRD1 for treatment of obesity. To accomplish this, assays that have been used successfully at Progenra to discover molecules that are active against other physiologically relevant E3 ligases will be adapted to screen for novel HRD1 inhibitors for characterization and development as therapeutic agents for obesity. Selected hits from the screen of Progenra's small molecule collection will be evaluated for predicted physiological activity in cellular models (based on PCG1?-associated cell markers developed by Progenra's collaborator Professor Toshihiro Nakajima of Tokyo Medical University). In Phase II, selected molecules with acceptable chemical properties and cell based activity will be put into pre-clinical development for anti-obesity therapy.